tbuckley/cabot-search huggingface dataset:
NCOG-39. DISCOVERY OF CLINICAL AND DEMOGRAPHIC DETERMINANTS OF SYMPTOM BURDEN IN PRIMARY BRAIN TUMOR PATIENTS USING NETWORK ANALYSIS AND UNSUPERVISED CLUSTERING
Authors: Brandon Bergsneider, Elizabeth Vera, Ophir Gal, Alexa Christ, Amanda King, Alvina Acquaye, Anna Choi, Heather Leeper, Tito Mendoza, Lisa Boris, Eric Burton, Nicole Lollo, Marissa Panzer, Marta Penas-Prado, Valentina Pillai, Lily Polskin, Jing Wu, Mark Gilbert, Terri Armstrong, Orieta Celiku
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Precision health approaches to managing symptom burden in primary brain tumor (PBT) patients are imperative to improving patient outcomes and quality of life. Network Analysis (NA) identifies complex symptom co-severity patterns across large patient cohorts. Unsupervised clustering unbiasedly stratifies patients into clinically relevant subgroups based on symptom patterns. This is the first study to use NA and unsupervised clustering to explore PBT patients’ clinical and demographic determinants of symptom burden. METHODS Symptom severity data reported using the MDASI-BT from a two-institutional cohort of 1,128 PBT patients was analyzed. Gaussian Graphical Model networks were constructed for the entire cohort and for subgroups identified by unsupervised clustering. Network characteristics were analyzed and compared using permutation-based statistical tests. RESULTS NA on the entire cohort revealed that the majority of PBT patients experience symptoms on four core dimensions that drive overall symptom burden: cognitive, physical, focal neurologic, and affective. These dimensions substantially overlap with factor groupings defined during initial construct validation of the MDASI-BT. Fatigue/drowsiness scored the highest in all network centrality measures, indicating a pivotal role in the symptom experience. Unsupervised clustering identified four patient subgroups: PC1 (n = 683), PC2 (n = 244), PC3 (n = 92), and PC4 (n = 109). Moderately accurate networks could be constructed for PC1 and PC2, but not for PC3 and PC4 due to their small size. The PC1 network closely resembles the all-patient network, and these patients have the highest interference scores among the subgroups with fatigue/drowsiness as the primary driver. PC2 represents an older subgroup in which cognitive symptoms drive symptom burden. CONCLUSIONS This novel study identified clinically relevant subgroups of patients with unique symptom burdens. With further validation, our approach may inform more personalized and effective symptom management by identifying symptoms to prioritize for targeting in individual patients.
EXTH-28. INTRATUMORAL HETEROGENEITY OF THERAPEUTIC VULNERABILITIES ACROSS ENHANCING AND NON-ENHANCING TUMOR COMPONENTS OF GLIOBLASTOMA: A PARADIGM-SHIFTING PERSONALIZED MEDICINE APPROACH
Authors: Wan-Hsin Lin, Diogo Moniz-Garcia, Ryan Feathers, Mieu Brooks, Erik Middlebrooks, Lindsey Kinsella, Kaisorn Chaichana, Alfredo Quiñones-Hinojosa, Panos Anastasiadis
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) is the most aggressive adult brain tumor with no effective therapy. Despite advances on its molecular characterization, targeted therapeutics remain out of reach. This lack-of-progress is largely attributed to molecular and spatial heterogeneity and absence of clinically applicable models to guide patient care. Moreover, as standard surgical resection is aimed at contrast-enhancing (CE) tumor, the molecular landscape and treatment response of the remaining non-contrast enhancing (nCE) component is largely unknown despite its active role in tumor progression and local recurrence. Here, we aimed to identify the functional impact of tumor heterogeneity and to explore therapeutic vulnerabilities of both CE and nCE components. Four tumor regions (two CE and two nCE) from each of five GBM patients were collected under neuronavigation. The resulting tissue was subjected to generation of 3D tumor models (a brain tumor initiating-enriched cell line and a spheroid-based mcancer model) with comparable success in both CE and nCE samples. A panel of 25 brain penetrant drugs (alone and in combination) targeting GBM drivers (i.e. RTK/Ras/PI3K, RB/cell cycle, p53/apoptosis, DNA damage repair, transcription addiction) was developed and used to test for therapeutic vulnerabilities. From each tumor region, 4.5 ± 3.7 (average ± SD) different targeting strategies were identified exhibiting at least 70% growth inhibition at Cmax. Drug response heterogeneity was relatively rare, varied among cases, and was independent of tumor enhancement status. To our knowledge, this is the first study to systemically assess treatment response from both CE and nCE patient-derived GBM models. Ongoing studies include comprehensive genome and transcriptome profiling and pathway analysis from these different tumor regions. We postulate that interrogation of molecular landscapes and vulnerability profiles of both CE and nCE tumor regions, will enable us to personalize and prioritize effective targeted interventions for GBM treatment.
CNSC-36. VRK1 IS A PARALOG SYNTHETIC LETHAL TARGET IN VRK2-METHYLATED GLIOBLASTOMA
Authors: Julie Shields, Samuel Meier, Madhavi Bandi, Maria Dam Ferdinez, Justin Engel, Erin Mulkearns-Hubert, Nicole Hajdari, Binzhang Shen, Christopher Hubert, Kelly Mitchell, Wenhai Zhang, Shan-chuan Zhao, Alborz Bejnood, Minjie Zhang, Robert Tjin Tham Sjin, Erik Wilker, Justin Lathia, Jannik Andersen, Yingnan Chen, Fang Li, Barbara Weber, Alan Huang, Natasha Emmanuel
Journal: Neuro-Oncology (2022)

Abstract Synthetic lethality — a genetic interaction that results in cell death when two genetic deficiencies co-occur but not when either deficiency occurs alone — can be co-opted for cancer therapeutics. A pair of paralog genes is among the most straightforward synthetic lethal interaction by virtue of their redundant functions. Here we demonstrate a paralog-based synthetic lethality by targeting Vaccinia-Related Kinase 1 (VRK1) in Vaccinia-Related Kinase 2 (VRK2)-methylated glioblastoma (GBM). VRK2 is silenced by promoter methylation in approximately two-thirds of GBM, an aggressive cancer with few available targeted therapies. Genetic knockdown of VRK1 in VRK2-methylated GBM cell lines and patient-derived models was lethal and resulted in decreased activity of the downstream substrate Barrier to Autointegration Factor (BAF), a regulator of post-mitotic nuclear envelope formation. VRK1 knockdown, and thus reduced BAF activity, caused nuclear lobulation, blebbing and micronucleation, which subsequently resulted in G2/M arrest and DNA damage. The VRK1-VRK2 synthetic lethal interaction was dependent on VRK1 kinase activity and was rescued by ectopic VRK2 expression. Knockdown of VRK1 led to robust tumor growth inhibition in VRK2-methylated GBM xenografts. These results indicate that inhibiting VRK1 kinase activity could be a viable therapeutic strategy in VRK2-methylated GBM.
SURG-27. THERAPEUTIC OPTIONS FOR RECURRENT GLIOBLASTOMA-EFFICACY AND SAFETY OF TALAPORFIN SODIUM MEDIATED PHOTODYNAMIC THERAPY WITH MAXIMAL RESECTION
Authors: Yoshihiro Muragaki, Tatsuya Kobayashi, Masayuki NItta, Kazuhide Shimizu, Takakazu Kawamata
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Recurrent glioblastoma (GBM) remains one of the most challenging clinical issues, with no standard treatment and effective treatment options. METHODS To evaluate the efficacy of talaporfin sodium (TS) mediated photodynamic therapy (PDT) as a new treatment for this condition, we retrospectively analyzed 70 patients who underwent surgery of maximal resection with PDT (PDT group) for recurrent GBM and 38 patients who underwent surgery of maximal resection alone (control group). RESULTS The median progression-free survival (PFS) in the PDT and control groups after second surgery was 5.7 and 2.2 months, respectively (p = 0.0043). The median overall survival (OS) after the second surgery was 16.0 and 12.8 months, respectively (p = 0.031). Both univariate and multivariate analyses indicated that surgery with PDT and a preoperative Karnofsky Performance Scale were significant independent prognostic factors for PFS and OS. In the PDT group, there was no significant difference regarding PFS and OS between patients whose previous pathology before recurrence was already GBM and those who had malignant transformation to GBM from lower grade glioma. PDT was well tolerated by all patients and in no case did treatment-related severe adverse effects. There was also no significant difference in TS accumulation in the tumor between these two groups. CONCLUSION According to these results, additional PDT treatment for recurrent GBM could have potential survival benefits and its efficacy is independent of the pre-recurrence pathology.
EPID-16. SEASONAL INCIDENCE PATTERN COMPARISON BETWEEN PRIMARY AND SECONDARY CENTRAL NERVOUS SYSTEM LYMPHOMAS
Authors: Rachel Yang, Alexis Demopoulos, Jianyi Li
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVE To compare primary CNS lymphoma [PCNSL] and secondary CNS lymphoma [SCNSL] incidence by year, month, week, and time between symptom onset, radiographic study, and tissue diagnosis. BACKGROUND PCNSL is a rare non-Hodgkin’s B-cell lymphoma confined to the central nervous system with an increased incidence among immunocompromised patients and immunocompetent patients.1 Epstein Barr Virus [EBV] infection usually accompanies immunocompromised patients with PCNSL. Whether viral infection is etiologic remains uncertain, especially among the immunocompetent, where EBV is not found. A seasonal pattern was described suggesting an infectious etiology.2 We sought to add to the literature our experience regarding patterns of disease onset. Design/ METHODS We retrospectively identified 96 immunocompetent PCNSL patients and 75 SCNSL patients treated here between 2010-20. Complete data was available for 91 PCNSL and 73 SCNSL patients. Variables collected included symptom onset, initial imaging, and tissue collection dates. RESULTS Weekly incidence was noted in both, with peak of incidence in the 10th and 40th week in PCNSL in 9th, 27th, and 31st weeks among SCNSL. Time between symptom onset and first neuroimaging study was significantly different, with PCNSL patients having significantly less time on average. Curiously, the average time between each PCNSL diagnosis was significantly shorter than that for SCNSL diagnosis. CONCLUSION/RELEVANCE Due to the rarity of the disease, larger studies are needed to further elucidate potential viral etiologies underlying PCNSL.
TMIC-05. SINGLE-CELL MULTI-OMIC ANALYSIS OF SPORADIC VESTIBULAR SCHWANNOMAS REVEALS SCHWANN CELLS WITH AN INJURY PHENOTYPE AND AN ASSOCIATION BETWEEN TUMOR SIZE AND MACROPHAGE INFILTRATE
Authors: Bhuvic Patel, Thomas Barrett, Sangami Pugazenthi, Saad Khan, Aldrin Yim, Craig Buchman, Akash Patel, Allegra Petti, Sid Puram, Albert Kim
Journal: Neuro-Oncology (2022)

Abstract Vestibular schwannomas (VS) comprise 8% of primary brain tumors, with rising prevalence due to increased detection by imaging. How intertumoral heterogeneity and differences within the tumor microenvironment (TME) contribute to the pathogenesis of VS remains poorly understood. We performed single-cell RNA sequencing (scRNA-seq) on 15 sporadic VS with paired single-nucleus assay of transposase accessible chromatin sequencing (snATAC-seq) on 7 tumors. Dimension reduction analysis revealed diverse Schwann, immune—predominantly macrophage, and stromal cell populations. Schwann cells adopted multiple unique functional states, such as repair-like, myelinating, and hypoxia-response, reflecting undescribed intratumoral heterogeneity within VS-associated Schwann cells. Remarkably, VS-associated Schwann cells were found to be phenotypically similar to Schwann cells in the setting of peripheral nerve injury, which is robustly associated with macrophage recruitment. Indeed, using our scRNA-seq atlas to perform deconvolution analysis of a broader cohort of VS, including newly sequenced (n = 22) and published bulk RNA-sequencing datasets (n = 153), we found variation in proportion of immune cells was strongly correlated with the proportion of macrophage infiltrate (R,2 = 0.86, p &amp;lt; 0.001). Furthermore, we found that macrophage/monocyte lineage cells represent a disproportionately large number of cycling cells in the VS TME, a finding corroborated by immunohistochemistry. Clinically, tumors with high macrophage infiltrate were associated with larger tumor size (Fisher’s exact test p = 0.007). Together, these findings suggest macrophages play an important role in VS pathogenesis. We therefore sought to characterize potential cell-to-cell interactions between Schwann cells and macrophages in our scRNA-seq atlas. Ligand-receptor analysis revealed several cytokines expressed by Schwann cells with cognate receptors expressed by macrophages, including MIF, SPP1, MDK, SEMA3C and IL34, which may be responsible for recruiting macrophages. In summary, we describe previously uncharacterized cellular diversity within VS, highlight an association between macrophage infiltration and clinical phenotypes, and identify potential therapeutic targets for VS treatment.
DDDR-02. CDK4/6 INHIBITION WITH ABEMACICLIB SENSITIZES INTRACRANIAL TUMORS TO CHECKPOINT BLOCKADE IN PRE-CLINICAL MODELS OF BRAIN METASTASIS
Authors: Naema Nayyar, Magali de Sauvage, Emily Sullivan, Jane Chuprin, Erika Yamazawa, Brehm Michael, Priscilla Brastianos
Journal: Neuro-Oncology (2022)

Abstract Although immune checkpoint inhibitors (ICI) have become a useful tool in the management of central nervous system (CNS) metastases, only a subset of patients experience durable clinical responses and prognosis continues to remain poor. In particular, the role of ICI for CNS metastases from breast cancer has also not been adequately explored. CDK4/6 inhibition has been shown to sensitize extracranial tumors to ICI, and we previously reported intracranial efficacy of combination CDK4/6 inhibition with abemaciclib and anti-PD-1 in preclinical models of melanoma brain metastasis. We have now investigated this combination strategy further in a mouse model of triple negative breast cancer brain metastasis. 4T1 mammary carcinoma cells were first injected into the mammary fat pad and then intracranially 3 days later. While single agent anti-PD-1 antibody or abemaciclib were both ineffective at reducing tumor growth, we found a significant reduction in intracranial and extracranial tumor burden when abemaciclib was combined with anti-PD-1. Immunofluorescence for CD8 and CD3 revealed a significant increase in tumor-infiltrating CD8+ T cells with abemaciclib monotherapy as well as combination therapy in intracranial 4T1 tumors. We observed a similar increase in intracranial tumor-infiltrating CD8+ T cells in two melanoma brain metastasis models, YUMM1.7 and B16-F10, following combination therapy. We conclude that combination with abemaciclib can improve intracranial efficacy of ICI by driving CD8+ T cell infiltration into intracranial tumors. Future work will focus on investigating additional treatment-induced changes in the tumor immune microenvironment and dissecting the effect of CDK4/6 inhibition on T cell activation and function.
DDDR-08. ARF4-MEDIATED RETROGRADE TRAFFICKING AS A MECHANISM OF CHEMORESISTANCE IN GLIOBLASTOMA
Authors: Shreya Budhiraja, Shivani Baisiwala, Ella Perrault, Sia Cho, Li Chen, Crismita Dmello, Cheol Park, Adam M Sonabend, Atique Ahmed
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) remains a deadly disease with an extremely poor prognosis, owing largely to its high rate of resistance to conventional temozolomide (TMZ) chemotherapy. To identify the unknown drivers of this chemoresistance, we performed a genome-wide CRISPR knockout sensitivity screen. Results showed significant enrichment of ~200 novel genes, including ARF4, a previously unstudied gene involved in retrograde trafficking—a well-regulated process by which cargo is transported internally from endosomes to ultimately the nucleus. Initial investigation showed that ARF4-knockdowns resulted in significantly heightened susceptibility to TMZ in multiple GBM patient-derived xenograft lines and extended survival compared to the controls (p&amp;lt; 0.01) in vivo in both primary and recurrent lines. Live-cell imaging further revealed that ARF4-knockdowns significantly inhibited retrograde trafficking, while ARF4-overexpressions resulted in an untenable increase in retrograde trafficking (p &amp;lt; 0.001) in vitro. Enhanced trafficking was also observed in TMZ-treated cells (p &amp;lt; 0.001), suggesting that ARF4 may drive dysregulation of retrograde trafficking to promote chemoresistance.We then performed an unbiased proteomics screen in control and ARF4-knockdown GBM cells with and without therapy to identify which proteins were being uniquely transported to the nucleus during therapy as a result of ARF4-mediated retrograde trafficking. Results showed the greatest enrichment of EGFR signaling, as validated by an increase in EGFR trafficking and nuclear EGFR expression in ARF4-overexpression and TMZ-treated conditions and a decrease of this phenomenon in ARF4-knockdown conditions.We also show that DNA-PK, a DNA repair protein that is transcriptionally activated by nuclear EGFR, is similarly downregulated in ARF4-knockdown conditions and elevated in ARF4-overexpression and TMZ-treated conditions. Treatment with DNA-PK-inhibitor, KU57788, resulted in extended survival compared to the controls (p &amp;lt; 0.01) in vivo in a recurrent line, indicating potential clinical benefit from targeting this pathway. Overall, we present a novel understanding of how ARF4 acts during therapy to increase nuclear localization of chemoresistance-promoting proteins.
DISP-12. RACIAL DISPARITY IN LENGTH OF STAY FOLLOWING CRANIOTOMY FOR PRIMARY BRAIN GLIOMA
Authors: Gavin Lockard, Jonah Gordon, Adam Alayli, Nam Tran
Journal: Neuro-Oncology (2022)

Abstract Introduction The racial disparities of opportunity to receive the appropriate surgical intervention and insurance coverage for adjuvant care may result in surgical outcome and survival disparities among different races. Length of stay (LOS) is an important quality metric measure for determining the distribution of medical resources and their consumption. This study aims to provide a perspective on racial disparities in the overall length of stay and complications for patients undergoing craniotomy for primary brain glioma. METHODS The authors performed a retrospective chart review of all patients who underwent craniotomies for resection of primary brain tumors at the Moffitt Cancer Center from 2004-2018. Patients age, race, tumor type, comorbidities, length of stay and complications were reviewed. RESULTS A total of 701 patients underwent craniotomies for primary brain glioma, but 66 were excluded due to insufficient follow-up or incomplete records. The racial categories include Caucasians, African American, Asian, Hispanic, and other. Due to the prevalence of Caucasians, the minorities groups were pooled as non-Caucasians. Both cohorts were similar in baseline comorbidities, KPS, tumor characteristics, and surgical factors. Mean LOS remained lower for Caucasians versus non-Caucasians (3.6 vs. 5.5 d). The differences in LOS remain among different tumor types, including GBM (4 vs. 6.7 d), anaplastic astrocytoma (2 vs. 4.4 d), and oligodendroglioma (2.3 vs. 3.7 d). Interestingly, among astrocytoma, Caucasians had a longer LOS (3 vs 1.2 d). CONCLUSION Our results highlight disparate treatment patterns that reflect in LOS among patients undergoing craniotomies for primary brain gliomas. These findings warrant further investigation regarding current health-care practices and policies.
STEM-21. REPURPOSING CLEMASTINE TO SUPPRESS GLIOBLASTOMA STEM CELLS
Authors: Michael Sun, Rui Yang, Heng Liu, Wenzhe Wang, Xiao Song, Bo Hu, Nathan Reynolds, Kristen Roso, Lee Chen, Paula Greer, Shi-Yuan Cheng, David Ashley, Christopher Pirozzi, Yiping He
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma stem cells (GSCs), also known as brain tumor initiating cells (BTICs), drive tumor progression, heterogeneity, and resistance to treatments, posing formidable challenges to advancing effective treatments against glioblastoma (GBM). We postulated that inducing BTIC differentiation can serve as a solution to diminishing their stem-like features. Here, we report that clemastine, an over-the-counter oral medication for allergy relief, attenuates stemness and proliferation of BTICs. These effects of clemastine were accompanied by altered transcriptional programs suggestive of a shift from maintaining stem cell identity to differentiation, resonating with the ability of clemastine to promote oligodendrocyte precursor cell (OPC) differentiation to mature oligodendrocytes. Genetic perturbation and small-molecule inhibition of putative pharmacological targets of clemastine revealed that Emopamil-binding protein (EBP), an enzyme in the sterol biosynthesis pathway, played a pivotal role in mediating the differentiating and anti-tumor effects of clemastine. Notably, loss-of-function assays showed that EBP expression was indispensable for BTIC propagation. In contrast, overexpression of EBP stimulated BTIC proliferation, thus uncovering a previously unknown role of sterol metabolism in BTIC maintenance. Finally, we demonstrated that a mouse neural stem cell-derived glioma model was similarly susceptible to clemastine treatment. Taken together, our study identifies pathways essential for the perpetuation of stemness in GBM, and implicates a non-oncology drug with a well-established safety profile that can be repurposed to mitigate the stem-like properties of GBM.